Colon carcinogenesis is thought to be a stepwise process that involves the transition of normal colon epithelium to neoplasm. The multistep progression of the disease requires years and possibly decades, and therefore apparently provides ample time for diagnosis and treatment. Unfortunately, however, 63% of colon cancer remains undetected until it has spread to the surrounding organs or lymph, a finding that correlates with a poor prognosis. In the gastrointestinal tract, conventional endoscopic techniques do not provide sufficient contrast for sensitive and reliable identification of early tumor disease.
One of the earliest recognizable events in the transition of normal colon epithelial cells into a carcinoma is the alteration of the cell kinetic processes of proliferation, differentiation, and apoptosis within the epithelial cells comprising the colon crypt. The zone of proliferation expands and ultimately encompasses the entire crypt. Moreover, the level of apoptosis is reduced and cannot balance the increased proliferation that occurs. The expansion of the proliferation zone is thought to result in the formation of a polyp that is composed of poorly-differentiated colonocytes and represents an intermediate stage in the development of a carcinoma. The transformation to carcinoma often is characterized by acquisition of an invasive phenotype wherein defective cells invade the underlying basement membrane.
Recent research has shed light on the genetic events that accompany the progression of normal colonic epithelium to neoplasm. In approximately 85% of sporadic colon cancers and in all inherited cases of familial adenomatous polyposis (FAP) forms of colon cancer have mutated adenomatous polyposis coli, APC. Further, in both sporadic tumors and FAP, mutations in APC were identified at the earliest stages of neoplasia, aberrant crypt foci These findings suggest that defects in the APC gene are the initiating event in the onset of the majority of colon tumors. In fact, APC appears to control colonic cell kinetics and seems to be involved in the first steps of colon carcinogenesis, particularly in the transition from normal to hyperproliferative coloncytes.
In light of the role played by the APC gene during colon tumorigenesis, it would be helpful to understand the functions of the APC protein. The APC protein is a large multidomain protein with many protein-protein interaction domains. It has been shown that APC binds to β-catenin, a protein that functions in cell adhesion and Wnt-based signal transduction. More than 90% of APC gene mutations inactivate the gene, resulting in premature termination of the transcript and subsequent truncation of the APC protein. Truncated APC proteins often retain the ability to dimerize and bind β-catenin, but lose the capacity to phosphorylate and alter intracellular levels of β-catenin and to bind to the microtubule cytoskeleton.
The failure of β-catenin levels to be properly regulated by proteasome degradation, and the subsequent increase of β-catenin-TCF complex formation results in an alteration of gene transcription. Functional β-catenin-TCF binding sites have been identified in the promoters of the cell cycle regulatory genes, cyclin D1 and c-myc and the overexpression of APC protein has been shown to block the cell cycle progression from the g0 and g1 phases to the s phase. Therefore, APC protein appears to have an important role in the regulation of colonic cell proliferation. Thus, the inactivation of the APC gene appears to disrupt both cell-cell and cell-matrix interaction, leading to inappropriate proliferation.
Through genetics, clinicians are able to identify patients that have an inherent risk for developing colon cancer. Although clinicians and researchers have identified an underlying molecular cause of colon cancer, this knowledge has translated into modest clinical success in the early diagnosis and treatment of colon cancer. Early work has focused on the use of antibodies for tumor recognition and drug delivery. However, when antibodies are used as the targeting molecule, the immunogenicity and long plasma half-life of these proteins were detrimental.
Currently, colon cancer detection methods are limited to recognition of relatively large abnormalities by visual inspection. Improved detection sensitivity through the use of diagnostic tools—such as high affinity peptides that exploit the molecular differences between normal, well-differentiated colonocytes and poorly-differentiated tumor cells—would be desirable.
It is apparent, therefore, that new methods that allow the accurate and convenient detection of neoplasms would dramatically extend life expectancy of many patients through disease prevention and are greatly to be desired. In particular, improved early detection methods that exploit the molecular differences between normal, well-differentiated colonocytes and neoplastic, poorly-differentiated colonocytes are highly desirable. Moreover, new methods of treating colon tumors are greatly to be desired.